Current analgesic therapies often fall short of therapeutic goals and typically have unacceptable side effects. In many chronic pain syndromes, such as those subsequent to neuropathic injury, pain is not well controlled by any currently available method. The sensation of pain is transduced in the periphery by pain-sensing, i.e. nociceptive, C- and A-delta primary afferent neurons. These neurons have a peripheral nerve ending in the skin or deep tissues and a central terminal that makes synaptic contact with second order neurons in the spinal cord dorsal horn. The impulse is processed locally for activation of withdrawal reflexes and relayed to the brain for conscious perception and contextually relevant integrated responses.
Vanilloid receptor-1 (VR1) is a multimeric cation channel prominently expressed in nociceptive primary afferent neurons (see, e.g., Caterina et al., Nature 389:8160824, 1997; Tominaga et al., Neuron 531-543, 1998). Activation of the receptor typically occurs at the nerve endings via application of painful heat (VR1 transduces heat pain) or during inflammation or exposure to vanilloids. Activation of VR1 by an agonist, such as resiniferatoxin or capsaicin, results in the opening of calcium channels and the transduction of pain sensation (see, e.g., Szalllasi et al., Mol. Pharmacol. 56:581-587, 1999.) After an initial activation of VR1, VR1 agonists desensitize VR1 to subsequent stimuli. This desensitization phenomenon has been exploited in order to produce analgesia to subsequent nociceptive challenge. For example, it has been shown that topical administration of resiniferatoxin (RTX), which is a potent vanilloid receptor agonist, at the nerve endings in the skin triggers a long-lasting insensitivity to chemical pain stimulation. Furthermore, it has been shown that both subcutaneous and epidural administration of the RTX produce thermal analgesia when administered to rats, with no restoration of pain sensitivity for over 7 days (see, e.g., Szabo et al., Brain Res. 840:92-98, 1999).
In these studies, however, the VR1 agonist was not administered directly to the nerve ganglion and the analgesic effect was reversible. Spatially, the peripheral Ca2+ toxicity is far removed from the neuronal perikarya in the ganglion so that application to the skin does not cause cell death. The present invention is based on the discovery that administration of VR-1 receptor agonist to the ganglion at the level of the neuronal cell body causes neuronal cell death and moreover, that the resulting selective ablation of VR1-containing neurons provides a treatment for chronic pain.
The effects of intrathecal capsaicin on thermal sensitivity in rats has also been investigated. The results, however, have been conflicting (Nagy et al., Brain Res. 211:497-502, 1981; Palermo et al., Brain Res. 208:506-510; Yaksh et al., Science 206:481-483, 1979; and Russell et al., Pain 25:109-123, 1986). Russell et al. observed no thermal analgesia, although in three previous studies, at least some degree of thermal analgesia was observed. The conflicting results raised a number of issues such as the possibility of complications in data interpretation resulting from spinal cord damage from cannula implantation, or solvent toxicity problems. Russell et al. therefore used a non-toxic solvent for capsaicin administration to rats and additionally, performed partial laminectomies to allow direct visualization of the cauda equina and thus insure drug delivery to the spinal fluid. No thermal analgesia was demonstrated and the authors concluded that intrathecal capsaicin administration is not a reliable method for producing thermal analgesia in the rat. The present inventors now resolve this controversy with the surprising discovery that intrathecal injection of a vanilloid receptor agonist such that the agonist contacts the neuronal cell body in an amount sufficient to cause Ca2+ influx, results in selective ablation of the neuron, and therefore is an effective therapy for chronic pain.
Recent studies have also shown that pain sensing C-fibers appear to participate in or exacerbate a variety of chronic diseases such as chronic pancreatitis, herpes infections, inflammatory or irritable bowel disease and rheumatoid arthritis. Generally, these chronic diseases have an inflammatory component in which the C-fibers play a role. The present invention therefore also provides a method of destroying C-fiber neurons that contribute to chronic disease syndromes, thus providing a method to ameliorate or resolve chronic inflammatory conditions. In addition, the ability to selectively kill VR-1-expressing neurons using the methods of the invention also provides a therapy for selectively removing neurons that are reservoirs of virus in chronic viral infections such as Herpes virus infection.